Prevention of tuberculosis among people with diabetes the first clinical trial globally

5 March 2020

Each year, more than 11 million people worldwide develop tuberculosis (TB), and more than 1.4 million die from the disease. In recent years it has become clear that diabetes is an important factor driving the global TB epidemic. Diabetes not only increasesthe risk of TB, but also leads to more severe and recurrent disease and more TB deaths. Globally, there are now an estimated 425 million people living with diabetes, but this number will increase significantly over the coming decades, especially in sub-Saharan Africa and other settings with a high burden of TB. As such, global TB control can only be successful if TB among people with diabetes is addressed. Soon, the first clinical trial to prevent TB among people with diabetes will be started by the PROTID consortium.

Tuberculosis – from latent infection to active disease
Two things need to happen for somebody to develop TB. First, people get infected with TB-bacilli, and second, infection needs to progress to TB disease, often some years later. It is estimated that one-fourth of the world population is infected with TB bacilli, but that only a small proportion will ever develop TB disease. Screening and preventive treatment of latent tuberculosis infection (LTBI) is considered essential for global TB control, and people with HIV have already been targeted for preventive treatment of LTBI. With short and effective treatment regimens available, the clear direction for global TB control is to expand preventive treatment to other high-risk groups.

People with diabetes as a risk group for TB
One such group is people with diabetes in countries with a high TB burden. Members of the PROTID consortium recently found that people with diabetes and LTBI almost had a four-fold increased risk of developing TB. Therefore, preventive treatment of LTBI among people with diabetes, if proven safe and effective, would help improve global TB control by reducing TB risk in this large risk group and limiting TB transmission to other people. Indeed, a recent mathematical model of TB-DM in India estimated that LTBI preventive treatment targeted at people living with DM (assuming 50% uptake), could prevent up to 11% of all new TB cases and 13% of TB deaths, with even larger effects expected over the coming decades.

The PROTID project
The PROTID consortium proposes to perform the first randomized controlled trial (RCT) globally to evaluate the efficacy and potential impact of preventive treatment of LTBI in people living with DM. Three-thousand people with DM and LTBI in Uganda and Tanzania will either get preventive treatment consisting of 12 weekly doses of a combination tablet rifapentine/isoniazid or placebo. They will be followed over two years to see if this treatment can prevent development of TB. In parallel to the trial, 1000 people with DM but without evidence of LTBI will be followed to confirm that the risk of TB in this group is indeed too low to warrant preventive treatment. In addition, PROTID will evaluate optimal ways to screen people with diabetes for LTBI and TB, among others using computer-assisted chest X-ray reading. It will also address gaps in prevention and therapeutic management of combined TB and diabetes in high-burden settings. Finally,it will estimate the impact and cost-effectiveness of treatment of LTBI in people living with diabetes on TB in the wider community.

The PROTID consortium, from science to policy change?
PROTID, which will run from January 2020 until July 2024, is part of the second ‘European and Developing Countries Clinical Trial Partnership’ (EDCTP), which is supported by the European Union. The PROTID consortium will be led by an experienced group of scientists and clinicians in the Netherlands, Uganda, Tanzania, United Kingdom and New Zealand. This first study will take place in sub-Saharan Africa, which is witnessing the fastest growth of diabetes globally, with the largest proportion of undiagnosed and poorly controlled disease. Members of PROTID have submitted a similar project for funding to be conducted in Asia, which currently carries the highest burden of combined TB and diabetes. If proven successful, the outcome of these two studies may help improveglobal policy and practice regarding prevention and management of combined TB and diabetes.